Case series of Pulmonary Alveolar Microlithiasis from India

Abstract

Pulmonary alveolar microlithiasis (PAM) is a rare disease characterised by calcific deposits in lung parenchyma. PAM being a progressive disease with dissociation between severity of clinical symptoms and radiological picture, it is often detected incidentally. Mutations in the SLC34A2 gene encoding the type IIb sodium phosphate cotransporter in alveolar type II cells are considered to be involved in the pathogenesis of PAM. The majority of the patients are diagnosed usually between the ages of 20 and 40 years, although paediatric PAM has also been reported. Diagnosis is confirmed by combination of radiological features, bronchial lavage and histopathological testing. At present, lung transplant is the only definitive treatment available. Though rare, the prevalence of PAM is worldwide. Till June 2018, 86 cases have been reported from India and 1042 cases have been reported worldwide. We report three cases from India, including a student, cement factory worker and a tailor, which will highlight the varied clinical and radiological presentations of this rare disease along with the response to treatment.

Background

Pulmonary alveolar microlithiasis (PAM) is a rare disease which is characterised by widespread intra-alveolar accumulation of minute calculi called microliths.¹

The first macroscopic description of this disease is attributed to Malpighi in 1686 in his work ‘In vesciculis pulmonum innumeri lapilli sunt’ (Lungs were heavy and compact with patches of black. Countless small stones were found in the interior of the lungs).²

In 1933, the disease was named as PAM by Hungarian pathologist Puhr.³ First case from India was reported in 1962 by Viswanathan.³

Here, we report three cases of this rare disease which emphasise on the myriad presentations of this disease.

Case presentation

Case 1

A 40-year-old man who has been working in a cement factory for past 15 years presented to the outpatient department of a tertiary hospital with dry cough for 3 years and breathlessness on exertion which progressed from modified Medical Research Council (mMRC) grade I to grade III over 3 years duration. He had no fever, chest pain or haemoptysis. He had no constitutional symptoms of loss of weight or decreased appetite. On enquiry, no significant family history was noted. He is a smoker with a smoking index of 140. His bowel bladder habits were normal and no significant comorbidities or past history of pulmonary infections were present. Clinical examination revealed tachycardia with pulse rate of 106/min, tachypnea with respiratory rate of 22/min, blood pressure of 150/100 mm Hg and hypoxaemia with SpO₂ at room air of 88%. He had central cyanosis and grade III clubbing. Respiratory system examination documented bilateral fine end inspiratory crackles predominantly in infrascapular, infra-axillary and mammary areas. Cardiovascular system examination documented left parasternal heave and loud pulmonary component of second heart sound. Hepatojugular reflex was positive. Other systems examination was unremarkable.

On investigation, his haemogram and biochemical profile were normal and his sputum was negative was infection and microliths. 2D Echo documented severe pulmonary hypertension with pulmonary arterial pressure of 68 mm Hg, dilated right atrium, right ventricle and main pulmonary artery. Arterial blood gas examination showed type 1 respiratory failure having moderate hypoxaemia with PaO₂ of 50.5 mm Hg. His chest X-ray showed bilateral reticular shadows with calcified micronodules (figure 1A). High-resolution CT (HRCT) chest was suggestive of bilateral interseptal thickening with calcification and lower lobe predominance (figure 2). Spirometry showed moderate restriction with severe reduction in diffusion capacity (table 1). Patient underwent a transbronchial lung biopsy which showed prominent basophilic concretions (ie, psammoma bodies) representing calcific foci within lung parenchyma which was consistent with PAM (figure 3A).

Figure 1.

Comparative chest radiographs of pulmonary alveolar microlithiasis showing varied involvement. (A) Chest X-ray (postero-anterior (PA) view) showing ’sand storm' appearance (case 1). (B) Bilateral reticulonodular shadows with calcifications (case 2). (C) Miliary pattern (case 3).

Figure 2.

CT chest showing interseptal thickening with calcifications and lower lobe predominance. Right upper lobe bulla is also noted as an incidental finding (case 1).

Table 1.

Lung functions in pulmonary alveolar microlithiasis

	Case 1	Case 2	Case 3
FEV1/FVC %	78.9	72.8	81.9
FVC	2.37 L (49.6)*	3.02 L (57.4)*	4.94 L (92.4)*
FEV1	1.87 L (49)*	2.20 L (52.8)*	4.05 L (90.8)*
RV	1.74 L (91.7)*	1.92 L (99.7)*	1.47 L (99.7)*
TLC	3.99 L (61.5)*	4.74 L (73.2)*	6.56 L (101.2)*
RV/TLC %	43 (150.37)*	40.50 (131)*	22.4 (118.4)*
DLCO (sb)†	5.82 (18.6)*	18.6 (61)*	30.45 (93)*

Lung function tests were made using Ganshorn Body Plethysmography Ganshorn PowerCube BODY + Reference predicted values are based on NHANES III (Hankinson—1999).

*Percentage of predicted values.

†mL CO /(min mm Hg).

DLCO (sb), diffusion lung capacity—single breath method; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; RV, residual volume; TLC, total lung capacity.

Figure 3.

Histopathological study of pulmonary alveolar microlithiasis. (A) H&E stained section shows prominent basophilic concretions (ie, psammoma bodies) representing calcific foci, within underlying lung parenchyma. Scattered mild lymphomononuclear inflammatory infiltrated noted in background (case 1). (B) Section shows occasional basophilic round to irregular concretions within underlying lung parenchyma, suggestive of calcific foci (case 2). (C) Alveoli filled with laminated concretions suggestive of microliths. Few patent alveoli show type II pneumocyte hyperplasia. Alveolar wall and interstitium appear normal (case 3).

Based on clinical, radiological and histopathological findings, a diagnosis of PAM was made and patient was managed with alendronate sodium (70 mg/week) along with inhaled bronchodilators (metered dose inhaler (MDI) tiotropium bromide 9 μg 2 puffs 24th hourly) He was advised smoking cessation and immunised with influenza and pneumococcal vaccination. Symptomatic improvement was noted over 6 months and has been advised regular follow-up to evaluate progression of the disease. His radiological changes remained static.

Case 2

A 42-year-old man, non-smoker, tailor by occupation, with no comorbidities, presented to the outpatient department with dry cough and progressive breathlessness on exertion of mMRC grade II for 3 years duration. He had no constitutional symptoms or chest pain, fever or haemoptysis. There was no significant family history. No significant past history of lung infections was noted. His general examination was within normal limits with pulse rate of 70/min, respiratory rate of 18/min, blood pressure of 118/70 mm Hg, without pallor, clubbing or cyanosis. His respiratory examination revealed bilateral fine end inspiratory crackles involving all lung fields while other systems examination was unremarkable.

On investigation, his haemogram and biochemical profile were within normal limits. Chest X-ray showed bilateral reticulonodular shadows (figure 1B). CT chest showed bilateral interseptal thickening with calcifications predominantly involving perihilar region and upper lobes of both lungs (figures 4 and 5). His spirometry was suggestive of moderate restriction with mild diffusion defect (table 1). Sputum examination for microliths was negative. Transbronchial lung biopsy showed occasional basophilic round to irregular concretions within underlying lung parenchyma, suggestive of calcific foci which was consistent with PAM (figure 3B).

Figure 4.

HRCT chest (mediastinal window) showing bilateral calcifications predominantly involving perihilar region and upper lobes (case 2). HCRT, high-resolution CT.

Figure 5.

HRCT chest (lung window) showing bilateral interseptal thickening with calcifications predominantly involving perihilar region and upper lobes (case 2). HCRT, high-resolution CT.

On the basis of above, he was managed with tablet alendronate sodium 70 mg/week for 1 year along with bronchodilators (MDI tiotropium bromide 9 μg 2 puffs 24th hourly) and vaccination against influenza and pneumococcus. He continues to be symptomatic improvement with over 1 year of follow-up although radiological changes remained static. He is being worked up for lung transplantation.

Case 3

A 21-year-old man, non-smoker, student, with history of pulmonary tuberculosis 1 year ago presented to the outpatient department with a 6-month history of dry cough and occasional streaky haemoptysis. He had no breathlessness, chest pain, fever or any constitutional symptoms and no significant family history, or personal history. His general examination was within normal limits with pulse rate of 90/min, respiratory rate of 18/min, blood pressure of 110/70 mm Hg, no evidence of hypoxaemia with SpO₂ at room air 97%. He had no pallor, clubbing or cyanosis. Respiratory system examination revealed bilateral end inspiratory crackles while other systems examination was unremarkable.

On investigation, his haemogram and biochemical profile were normal. Chest X-ray showed bilateral miliary nodules (figure 1C) and HRCT chest showed miliary nodules with few calcifications noted in perihilar region (figures 6 and 7). His spirometry was normal and diffusion study showed no reduction in transfer of gasses (table 1). A transbronchial lung biopsy documented alveoli filled with laminated concretions suggestive of microliths which was consistent with diagnosis of PAM (figure 3C).

Figure 6.

HRCT chest (mediastinal window) showing pericardiac calcification (case 3). HCRT, high-resolution CT.

Figure 7.

HRCT chest (lung window) showing pericardiac calcification along with miliary nodules predominantly in the lower lobes (case 3). HCRT, high-resolution CT.

He has been vaccinated against pneumococcus and influenza and is being managed with weekly alendronate sodium (70 mg/week) since past 2 months and is under follow-up.

Patient has been on treatment since 2 months as he has been kept under follow-up to identify the progression of disease.

Discussion

PAM is a rare, chronic disease of unknown aetiology characterised by the presence of extensive intra-alveolar calculi or microliths, spherical calcium and phosphate deposits, forming concentric lamellae surrounding an amorphous central nucleus measuring up to 2 µm in size.⁴

In a landmark review in 2015, 1022 case of PAM were reported worldwide till December 2014, including 80 from India.¹ Since then, 20 new case have been reported worldwide, including 6 from India till June 2018.

Gene responsible for PAM has been mapped to 4p15 and identified as SLC34A2 (solute carrier family 34 member A2).⁵ There is no specific gender predominance and it is seen across all ages from premature neonate to geriatric population, although it is more common in second and third decade of life.¹

Microlith formation is a result of phosphate-chelating action of calcium in extracellular fluid due to defect in SLC34A2 gene.⁵ SLC34A2 encodes a membrane protein of alveolar type II epithelial cells, which is the most important phosphate carrier in the lungs.⁶ During surfactant recycling and degradation, phosphate is released in alveolar space as a by-product of phospholipids. Wild-type IIb sodium–phosphate cotransporter transports phosphate into the cells. A mutant form of IIb sodium–phosphate cotransporter is a result of mutation in SLC34A2 gene and is unable to clear intra-alveolar phosphate.⁷

PAM patients have normal serum calcium and phosphorus levels.⁸ Lung histology shows intra-alveolar calcospherites and fibrosis of alveolar wall.⁹ Histologically microliths are periodic acid Schiff stain positive.¹⁰

Hallmark of PAM is its clinicoradiological dissociation wherein the symptoms often go unnoticed in contrast with radiological picture.¹¹

There are no symptoms in >50% of the patients as noted with our third case and the diagnosis is often fortuitous.^{5 12} Symptomatic patients often present with breathlessness and cough as primary complaints which was evident in the first two cases. Pathogenesis of cough is attributable to the stimulation of unmyelinated c fibres in the bronchial tree and lung parenchyma by microliths.^{12 13} Extrapulmonary manifestations including pericardiac calcifications as seen in our reported case have been documented.^{14 15}

Chest X-ray which is usually gives the first clue towards PAM as seen in first two of our cases often shows bilateral, diffuse, micronodular calcifications, often termed as ‘sand-storm’ appearance.^{6 12} The calcifications may be so dense, that the cardiac border, diaphragm, costophrenic an cardiophrenic angles may be obliterated.¹⁶ Radiological involvement is typically with lower lung field predominance, although cases have been reported with predominant perihilar distribution.¹⁰ In our second case, the involvement is predominantly in the upper lobes. HRCT chest appearances of PAM closely correspond to pathologic findings.⁴ On HRCT chest, perilobular and centrilobular distribution of calcifications is seen although subpleural, peribronchovascular and interlobular septal calcifications are also reported.¹⁷ In early disease and in children, ground glass opacities and interseptal thickening may be predominant, with calcifications being inconspicuous.¹⁸ Association between PAM and emphysema has been reported.¹⁹ The extent of interstitial changes correlate with pulmonary function abnormality, leading to the conclusion that pulmonary fibrosis is primarily contributory to the decline in lung functions.¹⁰ The differential diagnosis of PAM include miliary tuberculosis and other conditions leading to calcified micronodules such as sarcoidosis, silicosis, idiopathic and secondary haemosiderosis, amyloidosis and metastatic calcifications secondary to renal insufficiency wherein the correlation between clinical and radiological picture can lead to a confident diagnosis.⁴ In selected cases, HRCT may obviate need for transbronchial lung biopsy or bronchoalveolar lavage (BAL) to establish a diagnosis.⁴

Pulmonary function tests including spirometry, diffusion studies and arterial blood gas analysis may be normal in initial stages of the disease as was highlighted in our third case who has normal spirometry cored to moderate restriction in other two cases. As the disease progresses, a restrictive defect in the form of reduced total lung capacity and diffusion abnormalities with hypoxaemia may be evident.⁸

Presently, there is no definite treatment for PAM. Systemic steroids and therapeutic BAL have been reported to be ineffective.^{6 9} There have been some reports of benefit of using disodium etidronate.²⁰ It acts by inhibiting formation of new pulmonary calcium phosphate crystallisation and resolving previously formed calcifications.²¹ Lung transplantation has shown to be beneficial in PAM requiring supplemental oxygen.²²

Disease is often silent till respiratory insufficiency develops. The rate of progression is varied. In some patients, it remains static whereas in others it has been reported to progress to respiratory failure and cor pulmonale.^{1 23} Death typically occurs 10–15 years after diagnosis, at a mean age of fifth decade of life from respiratory failure due to cor pulmonale.⁶

Learning points.

• Pulmonary alveolar microlithiasis (PAM) can present with variety of clinical features.

• Reliable diagnosis of PAM can be made on radiological findings.

• No specific treatment is approved of PAM and further research needs to be directed towards it.